Cancers, or malignant tumors, which are characterized by indefinite cell proliferation and cell death, can be classified into three categories: carcinomas, sarcomas, and leukemia. Recent reports reveal that approximately one in eight women contracts breast cancer, while the risk of prostate cancer is about 9.5% among men over 50 years of age. (Helzlsouer, K. J. (1994) Curr. Opin. Oncol. 6:541-548; Harris, J. R. et al. (1992) N. Engl. J. Med. 327:319-328.) Cancer cells exhibit unique gene expression patterns, and numerous cancer-specific genetic markers, for example, tumor-associated antigens (TAAs), have been identified.
TAAs are surface molecules that are differentially expressed in tumor cells relative to non-tumor tissues. TAAs make tumor cells immunologically distinct from normal cells and provide diagnostic and therapeutic targets for human cancers. (Minegishi, M. et al. (1989) Leukemia Res. 13:43-51, Takagi, S. et al. (1995) Int. J. Cancer 61:706-715.) For example, the discovery of high level expression of the HER2 gene in breast tumors has led to the development of potential therapeutic treatments of breast cancer. (Liu, E. et al. (1992) Oncogene 7:1027-1032; and Kern, J. A. (1993) Am. J. Respir. Cell Mol. Biol. 9:448-454.)
TAAs have been characterized either as membrane proteins or altered carbohydrate moieties in glycoproteins and glycolipids, however the function of TAAs remain largely unknown. One TAA family, the transmembrane 4 superfamily (TM4SF), usually has four well-conserved membrane-spanning regions, certain conserved cysteine residues, and short sequence motifs. There is evidence that TM4SF antigens exist in close association with lymphocyte membrane receptors such as T cells CD4 and CD8 antigens. (Imai, T. and Yoshie, O. (1993) J. Immunol. 151:6470-6481.) Examples of TM4SF antigens include human melanoma-associated antigen ME491, human and mouse leukocyte surface antigen CD37, and human lymphoblastic leukemia-associated TALLA-1. (Hotta, H. et al. (1988) Cancer Res. 48:2955-2962; Classon, B. J. et al. (1989) J. Exp. Med. 169:1497-1502; and Tomlinson, M. G. et al. (1996) Mol. Immun. 33:867-872; Takagi, S. et al. (1995) Int. J. Cancer 61:706-715.)
Adenocarcinoma of the prostate accounts for a significant number of malignancies in men over 50, with over 122,000 new cases occurring each year in the United States alone. Prostate specific antigen (PSA) is a tissue-specific serine protease of the kallikrein family almost exclusively produced by prostatic epithelial cells. Expression of the PSA gene is regulated by androgens. The quantity of PSA correlates with the number and volume of the prostatic epithelial cells. Consequently, the levels of PSA are an excellent indicator of abnormal prostate growth. (Pearson et al. (1994) J. Urol. 152:1743-48.) Careful monitoring of PSA levels over time may provide one tool for detecting prostate cancer. Since PSA is also moderately elevated in patients with benign prostate hyperplasia, additional techniques are needed to distinguish between the two clinical conditions.
Cell and tissue growth is modulated by molecular interactions between growth activators and growth inhibitors. Expression of many growth activating leucine-rich proteins has been shown in developing and proliferating tissue. (Asundi, V. K. and Greher, K. L. (1992) Eur. J. Cell Biol. 59:314-321.) The broad function of the leucine-rich domain is thought to be associated with protein-protein interactions, in particular the leucine zipper motif. (Landschulz, W. H. et al. (1988) Science 240:1759-1764.) In addition, leucine-rich domains have been identified in transcription factor and non-transcription factor proteins. (Vanhaesebroeck, B. et al. (1997) Proc. Natl. Acad. Sci. 94:4330-4335.)
Apoptosis is a genetically controlled process by which unneeded or damaged cells can be eliminated. Apoptosis is initiated by growth inhibitors and by agents that antagonize growth activators. Disregulation of apoptosis has recently been recognized as a significant factor in the pathogenesis of human disease. For example, inappropriate cell survival can cause or contribute to many diseases such as cancer, autoimmune diseases, and inflammatory diseases. (Thompson, C. B. (1995) Science 267:1456-1462.) Proteins which induce apoptosis are termed pro-apoptotic and proteins which prevent apoptosis are termed anti-apoptotic. Anti-apoptotic proteins may contain regions which are homologous to those in pro-apoptotic proteins. (See O'Connor, L. et al. (1998) EMBO J. 17:384-395.)
The discovery of two new prostate growth-associated membrane proteins and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of neoplastic and reproductive disorders.